De novo acute myeloid leukemia risk factors: A Texas case-control study

BACKGROUND:

Acute myeloid leukemia (AML) is comprised of several bone marrow‐based cancers and is the most common type of leukemia in the United States. The etiology of AML is not well understood. A case‐control study was conducted at The University of Texas M. D. Anderson Cancer Center to investigate associations between lifestyle characteristics and the risk of AML in Texas.

METHODS:

This study included 638 adult patients with de novo AML (cases) and a group of 636 matched controls. Interviewer‐administered questionnaires were used to collect demographic and occupational data. The distribution of cases by World Health Organization (WHO) subtype was 71 patients (11%) with recurrent cytogenetic abnormalities (AML‐RCA), 134 patients (21%) with multilineage dysplasia (AML‐MD), and 389 patients (61%) with AML not otherwise categorized (AML‐NOC). Multivariate logistic regression analyses were performed among all AML cases and among both sexes and each WHO subgroup.

RESULTS:

Among men, heavy smoking (≥30 pack‐years; odds ratio [OR], 1.86) and occupational solvent exposure at low levels (OR, 2.87) or moderate/high levels (OR, 4.13) statistically significantly increased the risk of AML. Among women, obesity (OR, 1.62) and solvent exposure to low levels (OR, 2.73) or moderate/high levels (OR, 3.90) increased the risk of AML. Across WHO subtypes, obesity was associated with a statistically significantly increased risk of AML‐RCA (OR, 3.15), whereas solvent exposure increased the risk in all subtypes at low levels (AML‐RCA: OR, 4.11; AML‐MD: OR, 2.54) and moderate/high levels (AML‐RCA: OR, 5.13; AML‐MD: OR, 3.02). A joint effect between smoking and solvent exposure was observed, and the highest risk was observed among smokers who had solvent exposure (OR, 4.51).

CONCLUSIONS:

The current results suggested that several factors play a role in AML predisposition with possible joint effects. Risk profiles for AML differed by sex and WHO subtype. Cancer 2012. © 2012 American Cancer Society.     

Impact of erythropoietin on the reduction of blood transfusions and on survival of lung cancer patients receiving first-line chemotherapy

INTRODUCTION: Anaemia is a common problem in patients with cancer who receive chemotherapy and is normally associated with a negative impact on patients' quality of life (QOL), poor cancer control and diminished survival. In clinical trials, recombinant human erythropoietin has been shown to correct and prevent anaemia, decrease the need for blood transfusions and improve cancer patients' QOL. METHODS: A retrospective study followed lung cancer patients who received first-line chemotherapy in our hospital in 1998 and in 2005. The incidence of anaemia was analysed, as was the impact of incorporating erythropoietin into the treatment. RESULTS: The incidence of anaemia was 68% (69% of which reported asthenia) in 1998 vs. 54% (60% with asthenia) in 2005. The comparison of anaemia rates (1998 vs. 2005) were grade 1 (16% vs. 32%), grade 2 (36% vs. 16%), grade 3 (16% vs. 5%) and grade 4 (none). Treatment for anaemia included transfusion 52%, intravenous iron 5% and epoetin 4% in 1998. In 2005 anaemia was treated with transfusion 9%, intravenous iron 41%, and epoetin 49%. Median survival (1998 vs. 2005) was 242 days [95% confidence interval (CI) 217-329) vs. 356 days (95% CI 322-382). CONCLUSIONS: Erythropoietin is a valid alternative for cancer patients with anaemia undergoing chemotherapy. It can possibly avoid the need for transfusions without negatively impacting survival.     

Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System

BACKGROUND.: Recent studies have highlighted issues with the International Prognostic Scoring System (IPSS) model in relation to the exclusion of many subgroups that now represent a large proportion of patients with myelodysplastic syndrome (MDS) (eg, secondary MDS, chronic myelomonocytic leukemia [CMML] with leukocytosis, prior therapy) and its lack of applicability to most patients on investigational programs, because many would have received prior therapies and would have had MDS for a significant length of time. METHODS.: The authors analyzed 1915 patients with MDS who were referred from 1993 to 2005 (including those with CMML, secondary MDS, and MDS with prior therapy). Only 507 patients (26%) had primary MDS without prior therapy (ie, classifiable by the IPSS). Patients were divided randomly into a study group (n = 958) and a test group (n = 957). RESULTS.: A multivariate analysis of prognostic factors in the study group identified the following adverse, independent factors as continuous and categoric values (P<.001): poor performance, older age, thrombocytopenia, anemia, increased bone marrow blasts, leukocytosis, chromosome 7 or complex (>/=3) abnormalities, and prior transfusions. Cutoffs for anemia, thrombocytopenia and blasts, and cytogenetic subsets were different according to the IPSS. The new MDS prognostic model divided patients into 4 prognostic groups with significantly different outcomes. The model was validated in the test group. Applying the prognostic score of the new model within the 4 IPSS risk groups, overall, and in patients who had primary MDS without prior therapy was found to be highly prognostic in each subset. Applying the IPSS within each of the 4 risk groups of the new MDS model was not found to be prognostic. CONCLUSIONS.: The new model accounts for duration of MDS and prior therapy. It is applicable to any patient with MDS at any time during the course of MDS. Cancer 2008. (c) 2008 American Cancer Society.     

Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate.

PURPOSE: To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. MATERIALS AND METHODS: Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. RESULTS: Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% +/- 1.4% (mean +/- standard error of the mean) to 60.7% +/- 1.4% after 1 week, 50.9% +/- 2.4% after 2 weeks, and returned to 66.5% +/- 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% +/- 3.0% versus 26.8% +/- 2.7% in responders versus nonresponders (P = .007). CONCLUSION: Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.     

Outcome of patients with acute myelogenous leukemia after second salvage therapy

BACKGROUND: Although the prognosis is poor for patients with acute myelogenous leukemia (AML) who have disease recurrence after frontline therapy, this is a general reflection of first salvage therapies. The outcome of patients undergoing second salvage therapy in relation to complete response (CR) rates and survival has not been documented. The authors analyzed the outcome of patients with AML undergoing second salvage therapy, and identified prognostic factors associated with response and survival. METHODS: The records of 594 patients with AML undergoing second salvage therapy from 1980 until 2004 were reviewed. The patient median age was 50 years. Salvage therapy included allogeneic stem cell transplantation (SCT) in 74 patients, standard-dose cytosine arabinoside (ara-C) combinations in 30 patients, high-dose ara-C combinations in 171 patients, non-ara-C combinations in 73 patients, and Phase I-II single agents in 246 patients. RESULTS: Overall, 76 patients (13%) achieved CR. The median CR duration was 7 months. The median survival was 1.5 months, and the 1-year survival rate was 8%. A multivariate analysis of prognostic factors for CR identified the following 6 independent adverse factors: first CR duration < 6 months; second CR duration < 6 months; salvage therapy not including allogeneic SCT; non-inversion 16 AML; platelet counts < 50 x 10(9)/L, and leukocytosis > 50 x 10(9)/L. Patients were divided into low-risk (1-2 adverse factors; 8%), intermediate 1 (3 factors; 20%), intermediate 2 (4 factors; 38%), and high-risk groups (5-6 factors; 33%) with respective CR rates of 54%, 26%, 8%, and 0%. The respective 1-year survival rates were 36%, 21%, 6%, and 1%. A multivariate analysis for survival identified the following 7 independent adverse factors: first CR duration < 12 months; second CR duration < 6 months; bilirubin level > or = 1 mg/dL; albumin level < 3 g/dL; age > 60 years; bone marrow blasts > or = 50%; and year of therapy before 1991. Patients were divided into low-risk (0-2 adverse factors; 39%), intermediate (3 factors; 27%), and high-risk groups (> or = 4 factors; 34%) with estimated 1-year survival rates of 22%, 6%, and 0%, respectively. The respective CR rates were 26%, 8%, and 2%. CONCLUSIONS: The current analysis established the outcome and prognostic factors associated with second salvage therapy in AML. It also proposed risk models and groups that could be used for comparison of results of present and future investigational strategies.     

Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase: comparison with historic data

BACKGROUND: The International Randomized study of Interferon-alpha plus cytarabine (IFN-alpha plus ara-C) versus STI571 (imatinib mesylate) [IRIS trial] in patients with newly diagnosed Philadelphia chromosome (Ph)-positive, chronic-phase chronic myelogenous leukemia (CML) has not shown (to date) a survival advantage for imatinib. This was most likely because approximately 90% of patients receiving IFN-alpha plus ara-C changed to imatinib therapy after a median of 8 months into therapy. METHODS: The authors analyzed the results with imatinib therapy in patients with newly diagnosed Ph-positive CML in chronic phase and compared their outcome with patients who received IFN-alpha regimens. A total of 187 patients with Ph-positive CML in early chronic phase treated with imatinib were compared with a historic group of 650 similar patients treated with IFN-alpha regimens from 1982 until 1997. RESULTS: Patients who received imatinib were significantly older and had significantly more bone marrow basophilia and less leukocytosis. The complete cytogenetic response (Ph 0%) rates were better with imatinib (81% vs. 32%; P < 0.001), as were the survival rates (30-month estimated survival rates 98% vs. 88%; P = 0.01). A multivariate analysis of the total study group of 837 patients identified imatinib therapy to be a significant independent favorable prognostic factor for survival (P = 0.01). CONCLUSIONS: The current study is the first to indicate the survival advantage of imatinib compared with IFN-alpha, the previous standard of care, in patients with early chronic-phase CML.     

Multi-color CD34⁺ progenitor-focused flow cytometric assay in evaluation of myelodysplastic syndromes in patients with post cancer therapy cytopenia

Bone marrow assessment for myelodysplastic syndrome (MDS) in a patient who develops cytopenia(s) following cancer therapy is challenging. With recent advances in multi-color flow cytometry immunophenotypic analysis, a CD34(+) progenitor-focused 7-color assay was developed and tested in this clinical setting. This assay was first performed in 73 MDS patients and 53 non-MDS patients (developmental set). A number of immunophenotypic changes were differentially observed in these two groups. Based on the sensitivity, specificity and reproducibility, a core panel of markers was selected for final assessment that included increased total CD34(+) myeloblasts; decreased stage I hematogones; altered CD45/side scatter; altered expression of CD13, CD33, CD34, CD38, CD117, and CD123; aberrant expression of lymphoid or mature myelomonocytic antigens on CD34(+) myeloblasts; and several marked alterations in maturing myelomonocytic cells. The data were translated into a simplified scoring system which was then used in 120 patients with cytopenia(s) secondary to cancer therapy over a 2-year period (validation set). With a median follow-up of 11 months, this assay demonstrated 89% sensitivity, 94% specificity, and 92% accuracy in establishing or excluding a diagnosis of MDS.     

Predictors,utilization patterns,and overall survival of patients undergoing metastasectomy for metastatic renal cell carcinoma in the era of targeted therapy

Introduction

Metastasectomy (MSX) is considered a treatment option in patients with metastatic renal cell carcinoma (mRCC) at diagnosis, but its role in the targeted therapy era is unclear. We sought to describe the utilization trends of MSX and survival outcomes in a large US cohort.